Abstract Because many adverse effects of treatment for childhood cancer may not become clinically apparent until the survivor attains maturity or older ages, continued follow-up across the lifespan, from childhood through adulthood, is essential. With the number of childhood cancer survivors in the U.S approaching 500,000, there is a critical need to accurately characterize the development and manifestation of very late cancer-related sequelae. In late 2007, St. Jude Children?s Research Hospital initiated a unique clinical (i.e., medically evaluated) cohort with the primary aim of undertaking lifelong evaluation of health-related and quality of life outcomes in aging adult survivors of pediatric cancer. Eligibility for participation in the St. Jude Lifetime Cohort (SJLIFE) was initially defined as survival >10 years from diagnosis, and attained age of >18 years. With the award of the U01 Cohort Infrastructure grant (U01 CA195547) in July 2015, eligibility for the cohort was modified to include >5 year survivors. Participation rates for the cohort remain high with 80.4% of the 7152 contacted survivors having been successfully enrolled and an additional 6.8% with expressed interest in participating but pending an on-campus visit to provide informed consent. As of February 1, 2019, total enrollment on SJLIFE is 5753 survivors and 629 controls. Accomplishments over the 43 months since award of the U01 include: 2657 new participants enrolled, implementation of uniform medical assessments with 4096 on-campus clinical evaluations (reflecting performance of 263,165 clinical tests), banking of biospecimens for 94% of new participants (43,240 vials), germline whole genome sequencing of 4422 survivors, 22 active investigator-initiated funded grants utilizing the cohort, 22 active intervention-based trials, 27 data sharing collaborations, and 78 manuscripts submitted with 69 published/in press. In this competitive renewal application we propose to build upon these successes through activities to maintain and enhance the SJLIFE cohort as a unique and highly productive resource for pediatric cancer survivorship research and to directly: (1) facilitate an accelerated rate of discovery in survivorship research by establishing an innovative cloud-based data sharing platform to make clinical and genomic data from the SJLIFE cohort available to the global research community; (2) facilitate the investigation of genetic contributions to and pathophysiology of treatment-associated adverse long-term outcomes among survivors of childhood cancer; and, (3) facilitate establishment of a portfolio of validated risk prediction tools for clinical use in the management of pediatric cancer patients from the time of diagnosis through survivorship. The SJLIFE cohort will continue to be unique in its ability to provide new insights into the risks and pathophysiology of morbidity associated with cancer and its therapy, which is critical to the design of contemporary treatment protocols and public health initiatives to enable survivor access to preventive and remedial services.